Short-acting factor VII polypeptides

Abstract

Short-acting Factor VII peptides are disclosed. A shortened half-life is desirable for treatment of acute bleeding and similar disorders. Modification of the sialylation and/or glycosylation of Factor VII and variants thereof produced peptides useful in treating conditions of acute bleeding.

What is claimed is: 
     
       1. A method for treating a patient having a disease or a disorder wherein blood clot formation is desirable, comprising administering to the patient an effective amount of a human Factor VIIa polypeptide in which the ratio of moles of conjugated sialic acid to moles of N-linked glycan is less than 1.0; wherein the human Factor VIIa polypeptide comprises the amino acid sequence of SEQ ID NO: 16 and has glycans covalently attached at amino acid residues 145 and 322. 
     
     
       2. The method of  claim 1 , wherein the ratio of moles of conjugated sialic acid to moles of N-linked glycan is less than 0.1. 
     
     
       3. The method of  claim 1 , wherein the ratio of moles of conjugated sialic acid to moles of N-linked glycan is less than 0.05. 
     
     
       4. The method of  claim 1 , wherein the human Factor VIIa polypeptide contains no detectable amount of conjugated sialic acid. 
     
     
       5. The method of  claim 1 , wherein the half-life of the human Factor VIIa polypeptide is less than one hour. 
     
     
       6. The method of  claim 1 , wherein the half-life of the human Factor VIIa polypeptide is less than 0.5 hour. 
     
     
       7. The method of  claim 1 , wherein the disease or disorder is hemorrhage. 
     
     
       8. The method of  claim 1 , wherein the disease or disorder is selected from the group consisting of a hemorrhage, gastrointestinal bleeding, uncontrolled bleeding, bleeding while undergoing transplantation or resection or surgery, variceal bleeding, thrombocytopenia, hemophilia, intracranial hemorrhage, aortic aneurysm, and over administration of an anticoagulant. 
     
     
       9. A method of treating a patient having a blood clotting disorder that benefits from blood coagulation comprising:
 administering to the patient a therapeutically effective amount of a pharmaceutical formulation comprising a desialylated human Factor VIIa polypeptide comprising the amino acid sequence of SEQ ID NO: 16 and having glycans covalently attached at amino acid residues 145 and 322 and a pharmaceutically acceptable excipient or carrier. 
 
     
     
       10. The method of  claim 9 , wherein the desialylated human Factor VIIa polypeptide has no detectable sialic acid. 
     
     
       11. The method of  claim 9 , wherein the blood clotting disorder has acute bleeding. 
     
     
       12. The method of  claim 9 , wherein pharmaceutical formulation consists essentially of the desialylated human Factor VIIa polypeptide and one or more pharmaceutically acceptable excipients or carriers. 
     
     
       13. The method of  claim 9 , wherein the blood clotting disorder is not caused by congenital or developed clotting factor deficiencies or inhibitors to clotting factors. 
     
     
       14. The method of  claim 9 , wherein the blood clotting disorder that benefits from blood coagulation is selected from the group consisting of penetrating traumatic injury; blunt traumatic injury; bleeding in elective surgery; bleeding in cardiac surgery; bleeding in spinal surgery; orthopedic surgery; neurosurgery; oncology surgery; post-partum surgery; menorrhagia; bleeding in stem cell transplantation; bleeding in liver transplantation; gastrointestinal bleeding; active variceal bleeding in cirrhosis; non variceal bleeding in cirrhosis; diffuse alveolar hemorrhage; aortic aneurysm; intracerebral hemorrhage; traumatic brain injury; brain contusion; reversal of warfarin; reversal of heparin; reversal of anticoagulants; reversal of anti-thrombotics; Factor VII deficiency; burns; prophylaxis in hemophilia patients with inhibitors; partial hepatectomy for non-cirrhotic and cirrhotic patients; acquired hemophilia; idiopathic thrombocytopenic purpura; Glanzmann's Thrombasthenia; Glanzmann's Thrombasthenia refractory to platelet transfusion and Bernard-Soulier Syndrome.